Int J Physiol Pathophysiol Pharmacol 2010;2(2):104-110.
Original Article Tumor necrosis factor alpha signaling in the development of experimental murine pre-hepatic portal hypertension
Nicholas G. Theodorakis, Yining N. Wang, Jianmin Wu, Mary A. Maluccio, Nicholas J. Skill
Indiana University, Department of Surgery, Indianapolis, IN, 46202, USA
Received March 2, 2010, accepted March , 2010, available online March , 2010
Abstract: The cytokine tumor necrosis factor alpha (TNFα) has previously been identified in the development of portal hypertension (PHT) by facilitating portal venous and systemic hyperemia. TNFα is reported to contribute to hyperemia via endothelial nitric oxide synthase (eNOS) induction and nitric oxide (NO) production. This study examines this hypothesis by utilizing TNFα receptor knockout mice and a murine model of pre-hepatic PHT. Methods: Plasma TNFα and NOx and tissue TNFα mRNA levels were determined in wild- type mice 0-7d post induction of pre-hepatic PHT by partial portal vein ligation (PVL). TNFα receptor knockout mice also received PVL or sham surgery and splenic pulp pressure, abdominal aortic flow and portal-systemic shunting were recorded 7d following. Results: Portal pressure and systemic hyperemia developed rapidly following PVL. Plasma NOx was increased temporarily 2-3 days following PVL and returned to baseline by day 7. Circulating TNFα was below detectable limits of the ELISA used, as such no increase was observed. Hepatic and vascular TNFα mRNA levels were transiently changed after PVL otherwise there was no significant change. TNFα receptor targeted gene deletion did not ameliorate plasma NOx following PVL and had no effect on the development of PHT. Conclusion: TNFα receptor signaling plays no detectable role in the development of systemic hyperemia in the murine model of pre- hepatic PHT. Consequently, increased TNFα observed in intrahepatic inflammatory models (CCl4) and in patients is probably related to inflammation associated with intrahepatic pathology. Alternatively, TNFα may be signaling via a TNFα receptor independent mechanism. (IJPPP1002004).
Address all correspondence to: N. James Skill. PhD Indiana University Department of Surgery Wishard Hospital OPW425B 1001 W 10th St Indianapolis, IN, 46202 Tel (317) 274-2656 Fax (317) 274-7334 E-mail: nskill@iupui.edu